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    Clinical Trial Results:
    An Open-Label, Multicenter, Randomized, Phase 1b/2 Study of E7080 (Lenvatinib) in Combination with Dacarbazine versus Dacarbazine Alone as First Line Therapy in Patients with Stage IV Melanoma

    Summary
    EudraCT number
    2009-016049-24
    Trial protocol
    GB   DE  
    Global end of trial date
    01 Nov 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Oct 2016
    First version publication date
    30 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-702
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01133977
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, New Jersey, United States, 07677
    Public contact
    Eisai Call Center, Eisai Inc., 1 888-422-4743,
    Scientific contact
    Eisai Call Center, Eisai Inc., 1 888-422-4743,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jun 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: Phase 1b: To define the safety, tolerability and maximum tolerated dose (MTD) of lenvatinib administered in combination with dacarbazine in participants with Stage IV melanoma. Phase 2: To evaluate the safety and tolerability of lenvatinib administered in combination with dacarbazine, compared with dacarbazine alone, in participants with Stage IV melanoma.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki, 2008 - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed participant consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Apr 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    97
    EEA total number of subjects
    91
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    57
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 16 participants were enrolled in the Phase 1b portion of the study; all 16 participants received study treatment. A total of 82 participants were randomized in the Phase 2 portion of the study and a total of 81 participants received treatment. In the Dacarbazine arm, one participant withdrew consent prior to receiving study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    16 mg Lenvatinib + Dacarbazine (Phase 1b)
    Arm description
    Participants received 16 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib tablets administered orally at doses of 16 mg, once daily continuously over 3 weeks (21 days) during each 21-day cycle.

    Arm title
    20 mg Lenvatinib + Dacarbazine (Phase 1b)
    Arm description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib tablets administered orally at doses of 20 mg, once daily continuously over 3 weeks (21 days) during each 21-day cycle.

    Arm title
    22 mg Lenvatinib + Dacarbazine (Phase 1b)
    Arm description
    Participants received 22 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib tablets administered orally at doses of 22 mg, once daily continuously over 3 weeks (21 days) during each 21-day cycle.

    Arm title
    20 mg Lenvatinib + Dacarbazine (Phase 2)
    Arm description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 20 mg (MTD/recommended Phase 2 dose as determined in Phase 1b of the study) administered once daily continuously over 3 weeks (21 days) during each 21-day cycle.

    Arm title
    Dacarbazine (Phase 2)
    Arm description
    Participants received dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.
    Arm type
    Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Dacarbazine (DTIC)-Dome
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dacarbazine (1000 mg/m^2) infusion over 60 minutes on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2)
    Started
    3
    7
    6
    42
    39
    Completed
    0
    0
    0
    3
    1
    Not completed
    3
    7
    6
    39
    38
         Death
    1
    1
    1
    7
    3
         Started a new line of therapy
    2
    6
    4
    25
    33
         Adverse event
    -
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    5
    1
         Lost to follow-up
    -
    -
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    16 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 16 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    22 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 22 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 2)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    Dacarbazine (Phase 2)
    Reporting group description
    Participants received dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group values
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2) Total
    Number of subjects
    3 7 6 42 39 97
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    72 ± 6.56 62.6 ± 9.45 55.8 ± 9.33 61 ± 11.32 58.8 ± 11.84 -
    Gender categorical
    Units: Subjects
        Female
    0 5 2 17 16 40
        Male
    3 2 4 25 23 57

    End points

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    End points reporting groups
    Reporting group title
    16 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 16 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    22 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 22 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 2)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    Dacarbazine (Phase 2)
    Reporting group description
    Participants received dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Subject analysis set title
    20 mg Lenvatinib + Dacarbazine (Phase 2)
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Reporting Group Description: Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit. Analysis Population Description: All randomized participants who received at least one dose of study drug without major protocol eligibility violations were included in the Modified Intent-to-Treat (MITT) Analysis Set.

    Subject analysis set title
    Dacarbazine (Phase 2)
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Reporting Group Description: Participants received dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit. Analysis Population Description: All randomized participants who received at least one dose of study drug without major protocol eligibility violations were included in the MITT Analysis Set.

    Primary: Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b)

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    End point title
    Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) [1] [2]
    End point description
    DLTs were defined as clinically significant adverse events (AEs) occurring less than or equal to 21 days after commencing study treatment and considered by the Investigator to be possibly or probably related to study treatment.
    End point type
    Primary
    End point timeframe
    From Day 1 through 21 days (one cycle)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of this outcome measure is applicable for Phase 1 of the study.
    End point values
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b)
    Number of subjects analysed
    3
    7
    6
    Units: Participants with DLT
        Participants with DLTs
    0
    1
    2
        Grade 3 hypertension
    0
    1
    1
        Grade 3 febrile neutropenia
    0
    0
    1
        Grade 3 thrombocytopenia
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs)

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    End point title
    Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) [3]
    End point description
    Safety assessments consisted of monitoring and recording all AEs, including all Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) grades, and SAEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. Details of AEs and SAEs are provided in the reported adverse event section.
    End point type
    Primary
    End point timeframe
    From date of administration of first dose up to 30 days after the last dose, up to approximately 2 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study group and the study drug administered for this outcome.
    End point values
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2)
    Number of subjects analysed
    3
    7
    6
    42
    39
    Units: Participants
        AEs
    3
    7
    6
    40
    31
        SAEs
    2
    4
    2
    16
    1
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) (for Phase 2)

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    End point title
    Progression Free Survival (PFS) (for Phase 2)
    End point description
    PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression of such participant's disease based on Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST v. 1.1) or (2) the date of such participant's death due to any cause. Progression was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions, based on Investigator assessment according to RECIST 1.1. If missing assessments, imputed dates were used in the analysis.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of disease progression or death (whichever was earlier), up to approximately 2 years
    End point values
    20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2)
    Number of subjects analysed
    40
    37
    Units: Weeks
        median (confidence interval 95%)
    19.1 (9.57 to 25.57)
    7 (5.57 to 15.57)
    Statistical analysis title
    Hazard Ratio
    Comparison groups
    20 mg Lenvatinib + Dacarbazine (Phase 2) v Dacarbazine (Phase 2)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.75
    Notes
    [4] - The current study was not powered or designed to determine superiority of the '20 mg Lenvatinib + Dacarbazine (Phase 2)' arm compared with 'Dacarbazine (Phase 2) ' arm.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of administration of first dose up to 30 days after the last dose, up to approximately 2 years
    Adverse event reporting additional description
    Treatment emergent adverse events (TEAEs), defined as an AE that started/increased in severity on/after the first dose of study drug up to 30 days after final dose of study drug are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    16 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 16 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    22 mg Lenvatinib + Dacarbazine (Phase 1b)
    Reporting group description
    Participants received 22 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    20 mg Lenvatinib + Dacarbazine (Phase 2)
    Reporting group description
    Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Reporting group title
    Dacarbazine (Phase 2)
    Reporting group description
    Participants received dacarbazine (1000 mg/m^2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit.

    Serious adverse events
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 7 (57.14%)
    2 / 6 (33.33%)
    16 / 42 (38.10%)
    1 / 39 (2.56%)
         number of deaths (all causes)
    1
    1
    1
    7
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Physical disability
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intertrigo candida
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    16 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 1b) 22 mg Lenvatinib + Dacarbazine (Phase 1b) 20 mg Lenvatinib + Dacarbazine (Phase 2) Dacarbazine (Phase 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    40 / 42 (95.24%)
    31 / 39 (79.49%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    0
    2
    4
    Hypertension
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 7 (85.71%)
    5 / 6 (83.33%)
    20 / 42 (47.62%)
    2 / 39 (5.13%)
         occurrences all number
    1
    32
    23
    66
    2
    Hypertensive crisis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    4 / 42 (9.52%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    5
    0
    Phlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vasculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    7 / 42 (16.67%)
    7 / 39 (17.95%)
         occurrences all number
    1
    5
    1
    23
    8
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    1
    0
    0
    3
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    5 / 7 (71.43%)
    2 / 6 (33.33%)
    10 / 42 (23.81%)
    7 / 39 (17.95%)
         occurrences all number
    2
    11
    12
    20
    9
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infusion site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    4 / 42 (9.52%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    1
    7
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    7 / 42 (16.67%)
    1 / 39 (2.56%)
         occurrences all number
    0
    2
    0
    9
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Depression
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Disorientation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    1
    1
    1
    Reproductive system and breast disorders
    Breast disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Barotrauma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    0 / 6 (0.00%)
    5 / 42 (11.90%)
    3 / 39 (7.69%)
         occurrences all number
    0
    5
    0
    7
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    0
    5
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    0
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    6
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    1 / 39 (2.56%)
         occurrences all number
    0
    4
    0
    22
    1
    Weight decreased
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    5
    1
    0
    4
    0
    Cardiac disorders
    Conduction disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    5 / 42 (11.90%)
    4 / 39 (10.26%)
         occurrences all number
    0
    2
    1
    6
    4
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    1
    3
    0
    2
    2
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hiccups
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    0 / 39 (0.00%)
         occurrences all number
    2
    1
    0
    8
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    3 / 6 (50.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    3
    1
    1
    Pharyngeal erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    2 / 6 (33.33%)
    11 / 42 (26.19%)
    0 / 39 (0.00%)
         occurrences all number
    0
    3
    2
    14
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
    4 / 39 (10.26%)
         occurrences all number
    1
    0
    0
    4
    8
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    0
    2
    3
    Neutropenia
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    2 / 6 (33.33%)
    10 / 42 (23.81%)
    4 / 39 (10.26%)
         occurrences all number
    12
    7
    10
    15
    12
    Thrombocytopenia
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    2 / 6 (33.33%)
    5 / 42 (11.90%)
    1 / 39 (2.56%)
         occurrences all number
    5
    6
    3
    7
    1
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    0
    2
    0
    10
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    3 / 39 (7.69%)
         occurrences all number
    1
    1
    0
    3
    4
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    1 / 6 (16.67%)
    4 / 42 (9.52%)
    3 / 39 (7.69%)
         occurrences all number
    1
    6
    2
    5
    3
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Migraine
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    1 / 39 (2.56%)
         occurrences all number
    0
    0
    0
    3
    1
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    3
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    7 / 42 (16.67%)
    0 / 39 (0.00%)
         occurrences all number
    1
    4
    0
    17
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    5 / 42 (11.90%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    6 / 42 (14.29%)
    1 / 39 (2.56%)
         occurrences all number
    2
    3
    1
    7
    1
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    1 / 6 (16.67%)
    14 / 42 (33.33%)
    14 / 39 (35.90%)
         occurrences all number
    1
    7
    1
    39
    19
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    2 / 6 (33.33%)
    13 / 42 (30.95%)
    6 / 39 (15.38%)
         occurrences all number
    1
    8
    6
    33
    7
    Diverticulum
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    5 / 42 (11.90%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    5
    1
    Dyspepsia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    8 / 42 (19.05%)
    0 / 39 (0.00%)
         occurrences all number
    2
    4
    0
    9
    0
    Dysphagia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    0
    8
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    5 / 7 (71.43%)
    4 / 6 (66.67%)
    16 / 42 (38.10%)
    11 / 39 (28.21%)
         occurrences all number
    2
    14
    6
    37
    18
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    0
    3
    1
    3
    1
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 7 (57.14%)
    0 / 6 (0.00%)
    10 / 42 (23.81%)
    4 / 39 (10.26%)
         occurrences all number
    2
    15
    0
    24
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    8 / 42 (19.05%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    0
    26
    3
    Renal impairment
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences all number
    0
    0
    1
    2
    1
    Erythema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    2 / 39 (5.13%)
         occurrences all number
    1
    0
    0
    3
    2
    Pain of skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    4
    1
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    3 / 42 (7.14%)
    0 / 39 (0.00%)
         occurrences all number
    1
    3
    1
    5
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
    1 / 39 (2.56%)
         occurrences all number
    0
    5
    3
    5
    1
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    7 / 42 (16.67%)
    3 / 39 (7.69%)
         occurrences all number
    1
    4
    1
    7
    3
    Joint swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    1
    6
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    1 / 39 (2.56%)
         occurrences all number
    0
    0
    0
    3
    1
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    0
    2
    3
    Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    5 / 42 (11.90%)
    2 / 39 (5.13%)
         occurrences all number
    1
    7
    0
    6
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 7 (71.43%)
    0 / 6 (0.00%)
    10 / 42 (23.81%)
    1 / 39 (2.56%)
         occurrences all number
    1
    6
    0
    22
    1
    Dehydration
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    1
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
    1 / 39 (2.56%)
         occurrences all number
    0
    0
    0
    4
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Conjunctivitis viral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    0
    3
    0
    0
    1
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
    4 / 39 (10.26%)
         occurrences all number
    0
    2
    0
    3
    6
    Oral fungal infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
    0 / 39 (0.00%)
         occurrences all number
    0
    1
    1
    4
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
    3 / 39 (7.69%)
         occurrences all number
    3
    0
    0
    4
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2010
    Amendment 1, dated 19 May 2010: • Updated Sponsor’s phone number • Clarified that subjects experiencing clinical benefit following 8 cycles of study treatment may, at the discretion of the Investigator and in consultation with the Medical Monitor, continue dacarbazine with or without lenvatinib or single-agent lenvatinib • Clarified that follow-up was to be for up to one year after the End of Treatment • Clarified that dose reductions were not permitted in Cycle 1 of Phase 1b • Clarified the use of erythroid-stimulating agents • Added lymph nodes to the physical examination • Clarified that eCRFs would be used • Clarified that the Medical Monitor would be the contact person for any questions regarding treatment
    05 Nov 2010
    Amendment 3, dated 05 November 2010: • Clarified the definition of hypertension as a DLT • Clarified the dose reduction and interruption guidelines for lenvatinib (excluding hypertension) • Clarified the management guidelines for hypertension due to lenvatinib • Introduced a window of time allowed for obtaining Screening disease assessment (±5 days) • Clarified use of the IRT for assigning subjects to treatment groups • Revised the End of Treatment visit to occur on Day 30 (±3 days) and eliminated the Follow-up visit/phone call
    28 Feb 2013
    Amendment 5, dated 28 February 2013: Subject follow-up was changed from one year after the discontinuation of study drug to until death

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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